The church that burned Tuesday night was the historically black Hopewell Missionary Baptist Church in Greenville, a city of 35,000 people.
"The church was vandalised with the words 'Vote Trump' on the side," said mayor Errick Simmons at a press conference, describing the blaze as "a hateful and cowardly act".
Fire officials said the century-old church was fully engulfed in flames, and sustained heavy heat, smoke and water damage.
Related reading
Ku Klux Klan gives support, not endorsement to Trump
An investigation into the fire as a possible hate crime was under way by local, state and federal officials.
"This matter is a direct assault on people's right to freely worship," added Simmons.
Kristen Clarke, president and executive director of the Lawyers' Committee for Civil Rights Under Law, described the church as "a cornerstone of this majority-Black community located in the heart of the Mississippi Delta".
She also expressed concern that the church was vandalized so close to the November 8 presidential election.
"The toxic rhetoric of this election cycle continues to cast a dark cloud over this election cycle," Clarke said.
